title: Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia.
abstract: We analyzed somatic hypermutation (SHM) patterns and secondary rearrangements involving the immunoglobulin (IG) light chain (LC) gene loci in 725 patients with chronic lymphocytic leukemia (CLL). Important differences regarding mutational load and targeting were identified in groups of sequences defined by IGKV/IGLV gene usage and/or K/LCDR3 features. Recurrent amino acid (AA) changes in the IGKV/IGLV sequences were observed in subsets of CLL cases with stereotyped B-cell receptors (BCRs), especially those expressing IGHV3-21/IGLV3-21 and IGHV4-34/IGKV2-30 BCRs. Comparison with CLL LC sequences carrying heterogeneous K/LCDR3s or non-CLL LC sequences revealed that distinct amino acid changes appear to be "CLL-biased." Finally, a significant proportion of CLL cases with monotypic LC expression were found to carry multiple potentially functional LC rearrangements, alluding to active, (auto)antigen-driven receptor editing. In conclusion, SHM targeting in CLL LCs is just as precise and, likely, functionally driven as in heavy chains. Secondary LC gene rearrangements and subset-biased mutations in CLL LC genes are strong indications that LCs are crucial in shaping the specificity of leukemic BCRs, in association with defined heavy chains. Therefore, CLL is characterized not only by stereotyped HCDR3 and heavy chains but, rather, by stereotyped BCRs involving both chains, which generate distinctive antigen-binding grooves.
authors.affiliation: Institute of Agrobiotechnology, Centre for Research and Technology, Thessaloniki, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hadzidimitriou
authors.forename: Nikos
authors.initials: N
authors.lastname: Darzentas
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Tanja
authors.initials: T
authors.lastname: Smilevska
authors.forename: Eleni
authors.initials: E
authors.lastname: Arvaniti
authors.forename: Cristina
authors.initials: C
authors.lastname: Tresoldi
authors.forename: Athanasios
authors.initials: A
authors.lastname: Tsaftaris
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Laoutaris
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: Frederic
authors.initials: F
authors.lastname: Davi
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D001666:Binding Sites, Antibody / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000235:genetics* / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000235:genetics* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*
chemical_list: D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell